In spontaneously hypertensive rats (SHR) the hypersensitivity of the renal vasculature to angiotensin II (Ang II), compared to Wistar-Kyoto rats (WKY), appears to be the determining factor in the development and progression of hypertension. Recent evidence indicates that the ERK cascade and NAD(P)H oxidase generation of superoxide are involved in smooth muscle contraction, and Phospholipase D (PLD) generation of phosphatidic acid is involved in activation of ERK and NAD(P)H. Importantly, Ang II-mediated PLD activity is greater in aortic smooth muscle from SHR compared with WKY; however, this signaling pathway has not been examined in the kidney vasculature.
The purpose of these studies were to define Ang II-mediated signal transduction mechanism(s) involved in PLD regulation in WKY and SHR preglomerular smooth muscle cells (PGSMCs). The goals of this study were to determine: 1) whether Ang II-mediated PLD activity is greater in SHR; 2) the Ang II signaling pathway(s) responsible for regulating PLD activity, and whether they are altered in SHR; and 3) whether PLD-mediated generation of phosphatidic acid is involved in Ang II-induced activation of the ERK cascade.
The data indicates that the mechanisms leading to activation of PLD are similar in WKY and SHR and PLD is required for Ang II activation of ERK; however, Ang II more potently activates PLD in SHR. Further analysis indicates that the AT2 receptor inhibits AT1 receptor/RhoA-dependent activation of PLD through a nitric oxide/cGMP-dependent phosphorylation of RhoA at serine 188, which promotes RhoGDI inhibition of RhoA. These experiments expose two key differences between WKY and SHR PGSMCs: 1) SHR have an increased AT1/AT2 receptor ratio; and 2) SHR are less sensitive to nitric oxide and cGMP. Therefore, the hypersensitivity of the SHR to Ang II may be due to an imbalance in Ang II receptors and/or impaired AT2 receptor-mediated signaling within the kidney vasculature.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-06022002-180949 |
| Date | 26 September 2002 |
| Creators | Andresen, Bradley T. |
| Contributors | Peter A. Friedman, Ph.D., Guillermo G. Romero, Ph.D., Edwin K. Jackson, Ph.D., Daniel L. Altschuler, Ph.D, Gregg E. Homanics, Ph.D., Matthew F. Muldoon, M.D., M.P.H. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu:80/ETD/available/etd-06022002-180949/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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